Skin preparation

ABSTRACT

The invention concerns a skin preparation for moistening human skin comprising a combination of a component A and a component B, wherein A includes at least two saturated C 9 -C 31  fatty acids selected from the group consisting of iso- and anteiso fatty acids, whereby component B consists of cholesterol in an amount of 5-15% by weight of component A.

FIELD OF THE INVENTION

The present invention concerns a skin preparation. Specifically theinvention concerns a preparation for human skin improvement.

BACKGROUND OF THE INVENTION

Skin preparations have been used for thousands of years to render asofter and more elastic sensation of the skin. These preparations arebased on different components and work in different ways.

A frequently used component in skin preparations is lanolin, which iscomposed of hydrophobic esters, which oppose absorption of water.However, lanolin has been reported to cause allergic reactions in a highnumber of individuals.

Other frequently used components are water repellent films such aspetrolatum, which however may cause maceration by preventing even normalmoisture loss from the skin.

Furthermore, there are fats and oils of vegetable and animal origin,which are used in cosmetic formulations for their emollient, occlusiveand moisturizing properties. Stability problems with these productsrequire use of additives or stabilizers. These additives or stabilizersmay however cause dermal problems.

Phospholipids have also been used as moisturizers in various creams andlotions. These lipids are complex fat substances found in living cells.Lecithin is an example of a typical phospholipid substance.

Still another type of skin preparations is disclosed in WO 9831399,which concerns preparations capable of forming an osmotic i.e. semipermeable membrane in the skin. These preparations are based on acombination of a lipophilic component, such as a fatty acid (stearicacid) or polysiloxane, and a hydrophilic component, such astriethanolamine.

Another type of skin preparations is based on vernix caseosa, whichappears a cheesy deposit on the surface of human or animal foetuses andconsists of about ⅓ of cholesterol esters. This type of preparations isdescribed in e.g. U.S. Pat. No. 5,631,012 which concerns cosmeticcompositions containing naturally occurring and/or synthesized vernixlipid mixtures in the same proportionate mixture. These compositions aredescribed as moisturisers by functioning as a protective barrier betweenthe skin and the environment.

Preparations based on vernix caseosa are also known from JP 10175843,which describes a skin composition containing vitamin E and cholesterolesters of mammal vernix origin. A disadvantage with cholesterol estersis that they do not penetrate the skin, but stays on its surface.

Another publication concerning compositions including vernix isdisclosed in WO 99/44582. According to this publication a natural orsynthetic vernix is dispersed in a film-forming amount in abiocompatible liquid such as dimethylsulfoxid, amniotic fluid and/orpulmonary surfactant to form a film. This publication also recognisesthe problem of achieving a controlled and uniform administration of thevernix substances through the skin.

From the above patent publications and other literature it is thus knownthat vernix could have a potential as a beneficial agent in skinpreparations. A problem is however how to realize this effect and obtaina satisfactory effect.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide a pharmaceuticallyactive combination, which maintains the humidity and elasticity of humanskin and is rapidly absorbed by the skin.

Another object is to provide cosmetic and/or medical preparationsincluding this combination and conventionally used pharmaceutically anddermatologically acceptable carriers.

The formulations and methods by which the above objects may beaccomplished are disclosed hereinafter.

SUMMARY OF THE INVENTION

The present invention is based on the discovery that, if componentsextractable from vernix and other substances having similar compositionare combined with a specific amount of cholesterol, the problems withpreviously known skin preparations including such components/substancescan be reduced or eliminated and skin preparations having a beneficialeffect not previously observed on the skin are obtained. Specificallythe present invention concerns a skin preparation for moistening humanskin comprising a combination of a component A and a component B,wherein A includes at least two saturated C₉-C₃₁ fatty acids selectedfrom the group consisting of iso- and anteiso fatty acids, and wherebycomponent B consists of cholesterol in an amount of 5-15% by weight ofcomponent A. According to a preferred embodiment said iso-fatty acidsconstitute 30-70% by weight of component A and said anteiso-fatty acidsconstitute 70-30% by weight of component A.

DETAILED DESCRIPTION OF THE INVENTION

Specifically it has been found that component A, which ispharmacologically active, should be branched C₉-C₃₁ iso- andanteiso-fatty acids, preferably branched C₁₈-C₂₄ iso- and anteiso-fattyacids. These fatty acids have a low melting point giving high fluidityand are not easily oxidized. Due to the lower melting points of theanteiso- fatty acids it is presently believed that at least one of theat least two fatty acids should be an anteiso fatty acid. As an examplecomponent A could be made up by 12-methyltetradecanoic acid andisostearic acid and component B could be made up by 5-15, preferably8-12% by weight, of component A.

However, indications have also been found that preparations whereincomponent A is made up by two (or more) iso fatty acids without anyanteiso fatty acid(s) work satisfactorily. This is in accordance with myfinding that the absorption into the skin of the branched iso andanteiso fatty acids is better compared with ordinary fatty acids, i.e.olive oil that has a slow absorption. Branched fatty acids are rare innature, but are found in the form of cholesterol esters of the epidermisof the human skin where they also seem to have a key role in protectingthe membrane and may have a positive effect on the microcirculation.

In order to obtain full effect of component A, it has been found thatthe addition of cholesterol (component B) is important.

Test results have shown that the barrier properties of the skin increaseafter treatment with the skin preparation according to the inventionresulting in a decreased transepidermal water loss. Additionalexperimental studies have shown that the presence of cholesterolincreases the miscibility and decreases the area ratio phases of thecomponent A (measured by AFM, Atomic Force Microscopy), which in turnleads to a faster absorption when applied to the skin. The cholesterolcontent should be 5-15%, preferably 8-12%. The mechanism is probablythat cholesterol minimizes the interfacial length between differentphases.

Branched fatty acids useful in the skin preparations according to thepresent invention may be extracted from e.g. vernix caseosa, lanolin orbutter, but may also be made synthetically or produced from straightchain fatty acids. A method of preparation of branched fatty acid isdisclosed in WO 98/07680 and is hereby incorporated by reference.Another method for obtaining branched fatty acids which may be usedaccording to the present invention is disclosed in WO/98/30552 which isalso incorporated by reference.

The skin preparation may further comprise optional pharmaceutically anddermatologically acceptable excipients.

The physiologically active ingredient according to the invention isapplied on the skin at a suitable concentration in a suitabledermatologically acceptable carrier. The concentration of the activeingredient naturally depends on the type of preparation and the type andamount of vehicle(s) and adjuvant(s) included in the carrier. Naturally,the active ingredient i.e. the branched fatty acids must be applied tothe skin in a physiologically active amount.

The concentration of the branched fatty acids in a crème may be in therange 0.1-50% by weight, but is optimally in the range 10-30% by weight.An oil preparation may contain up to 90% by weight of the branched fattyacids.

The relative amount of the different branched fatty acids may be as inthe cholesterol esters found in vernix caseosa or lanolin or may be aselection at least two of them.

A preliminary study has shown that the preparation according to theinvention has an anti-inflammatory effect and may reduce/treat eczema.

EXAMPLES Example 1

The following example is a description of the extraction of branchedfatty acids from cholesterol esters in lanolin.

The lanolin used was Medilan liquid ultra™ from Croda Ltd Japan. 4 g oflanolin was accurately weighed into a 250 ml conical flask. 50 ml ofethanolic potassium hydroxide (0.5 mol/l) was added and a refluxcondenser connected to the flask. The flask was heated and occasionallyshaken until the fat was completely dissolved. The solution was boiledunder reflux for 30 minutes. The solution was cooled and white crystalsformed and precipitated. The supernatant of the solution was neutralizedwith HCl (1 mol/l) to pH 5.5 and then centrifuged. The supernatant wasdecanted from the pellet containing fatty acids and the remainingethanol evaporated by rotation. The resulting concentration of thebranched fatty acids was about 70%.

The fatty acid containing pellet was used for a skin preparationaccording to the present invention.

Table I shows the branched fatty acids from the fatty acid analysis ofMedilan liquid Ultra™.

TABLE I Results (% of total fatty acids) Standard sample 1 Sample 2Sample 3 Sample 4 C14:0 iso 11.5 3.3 2.9 4.8 C15:0 anteiso 16.6 7.2 6.49.6 C16:0 iso 8.8 9.5 8.5 8.3 C17:0 anteiso 5.0 6.5 6.2 4.9 C18:0 iso3.6 8.7 8.3 6.3 C19:0 anteiso 6.1 14.3 13.9 12.9 C20:0 iso 2.7 11.5 11.78.6 Total branched 54.3 61.0 57.9 55.4 fatty acids (%)

Example 2

Table II and III show examples of preparations according to theinvention. The branched fatty acids were extracted from Medilan LiquidUltra™ from Croda Ltd Japan and mixed with an ointment based onUngventum™ from Merck Inc. The solution was obtained by heating theingredients to 50° C. and thereafter mixing them.

TABLE II Cream formula Amount Ingredient (% by weight) Concentratedbranched fatty 25 acids (from Medilan Liquid Ultra ™) Cholesterol 10Ungventum ™ 40 Distilled water 25

TABLE III Oil formula Amount % Ingredient by weight Concentratedbranched fatty 90 acids (from Medilan Liquid Ultra ™) Cholesterol 10

Example 3

The effect of the skin preparation on the barrier properties of the skinwas examined with Trans Epidermal Water Loss (TEWL) provided by ServomedAB, Varberg. TEWL was measured at four different occasions with oneminute intervals, where the mean value is reported. An oil with 90% byweight branched fatty acid and 10% by weight cholesterol was applied atthe back of the left hand while the right hand served as control(untreated). The TEWL was measured before and three hours after theapplication of the-preparation (Table IV). The room temperature and thehumidity were constant during the measurements.

TABLE IV TEWL (g/m²/h) Creme formula according to Control the invention(no treatment) Before After Before After 15.8 13.6 17.3 18.0 11.9 6.112.7 9.4 8.0 6.8 7.0 6.8 11.3 9.2 13.0 12.7

The TEWL was significantly lower after the treatment with the activesubstance (p=0.03). In the control group there was no difference(p=n.s). As barrier function has been claimed to be improved with theuse of Fenuril™ hand lotion, the most selling skin cream on the marketat present and recommended by dermatologists, the product according tothe invention was compared with Fenuril™. The results of the TEWLmeasurements for Fenuril™ and an untreated control is described in TableV.

TABLE V TEWL (g/m²/h) Fenuril ™ treatment Control control (no treatment)Before After Before After 14.8 15.9 16.6 16.6 14.2 10.3 14.6 9.5

There was no difference in TEWL after the Fenuril™ treatment and nodifference in the control group (p=n.s).

Example 4

Five women used a skin preparation consisting of 90% branched fattyacids C₁₈-C₂₄ and 10% cholesterol for one week. All women had sufferedfrom skin dryness for several years and had extensive experience withskin preparations. The branched fatty acids were produced from a speciallanolin derivative (Medilan Liquid Ultra™). The skin preparation wasapplied at the back of the left hand and the right hand served ascontrol. The results were judged with regard to skin elasticity, skinsoftness and speed of absorption. The results were divided up into verygood, good, indifferent, bad and very bad. Four of the five womenexperienced the preparation as very good with regard to softness andelasticity. One experienced it as good. All women said that it wasquickly absorbed. No side effects occurred. Three of the womenexperienced positive results of the finger pulpa they had used whenapplying the preparation.

Example 5

1) The same set-up as in example 3 was used. Isostearic acid was mixedwith 12-methyltetradecanoic acid (anteiso C15) in equal parts. Theointment was divided in two parts, one without cholesterol and one mixedwith 10% of cholesterol. One drop of the sample without cholesterol wasapplied at the right and one drop of the sample with cholesterol wasapplied at the left hand back. The skin surface for the application was1 cm².

8 persons participated in the test, with mean age 48 years (62-37), 7women and one man. The absorption time between application andabsorption was measured and the result was statistically significantshorter for the ointment with cholesterol than for the one without asmeasured with Student T-test (p<0.01).

2) In this test the same compounds were used as in example 1, sample 2containing branched fatty acids of 61.0%. The ointment was divided intwo parts as in test 1) above, i.e. one sample with and one without 10%cholesterol. One drop of the two mixtures were tested on 1 cm² at theright and the left hand back as earlier. The same 8 persons as intest 1) participated in the test. Equivalent results were obtained asearlier, the ointment containing cholesterol was absorbed faster thanthe one without. The difference between the groups was statisticallysignificant (p>0.01).

The conclusion of these tests is subsequently that the presence ofcholesterol improve the absorption speed of the ointment on human skin.

3) 5 women underwent a test wherein isostearic acid and12-methyltetradecanonic acid were mixed in equal parts and 10%cholesterol was then added. The ointment was applied at the back of thehand and TEWL (trans epidermal water loss) was measured before and threehours after application. The other hand served as control. TEWL wasreduced with 18-34% after three hours compared with the controls were nodifference occurred.

1. A skin preparation for moistening human skin comprising a combinationof a component A and a component B, wherein A is a mixture of one ormore saturated C₉-C₃₁ iso fatty acid and one or more saturated C₉-C₃₁anteiso fatty acid, and wherein component B consists of cholesterol inan amount of 5-15% by weight of component A.
 2. The skin preparationaccording to claim 1 wherein the amount of cholesterol is 8-12% byweight of component A.
 3. The skin preparation according to claim 1,wherein component A is made up by 30-70% by weight of iso-fatty acid(s)and 70-30% by weight of anteiso fatty acid(s).
 4. The skin preparationaccording to claim 1, wherein the fatty acids of component A have 18-24C atoms.
 5. The skin preparation according to claim 1 wherein componentA is made up by 12-methyltetradecanoic acid and isostearic acid andcomponent B is 5-15% by weight of component A.
 6. The skin preparationaccording to claim 1, wherein component A comprises two iso fatty acids.7. The skin preparation according to claim 1, further comprising apharmaceutically and dermatologically acceptable excipient.
 8. The skinpreparation according to claim 1, in the form of an ointment.
 9. Theskin preparation according to claim 1, wherein the fatty acids originatefrom vernix caseosa, lanolin or butter.
 10. The skin preparationaccording to claim 2, wherein component A is made up by 30-70% by weightof iso-fatty acid(s) and 70-30% by weight of anteiso fatty acid(s). 11.The skin preparation according to claim 2, wherein the fatty acids ofcomponent A have 18-24 C atoms.
 12. The skin preparation according toclaim 3, wherein the fatty acids of component A have 18-24 C atoms. 13.The skin preparation according to claim 1, wherein component A is madeup by 12-methyltetradecanoic acid and isostearic acid and component B is8-12% by weight of component A.
 14. The skin preparation according toclaim 2, wherein component A comprises two iso fatty acids.
 15. The skinpreparation according to claim 2, further comprising a pharmaceuticallyand dermatologically acceptable excipient.
 16. The skin preparationaccording to claim 2, in the form of an ointment.
 17. The skinpreparation according to claim 2, wherein the fatty acids originate fromvernix caseosa, lanolin or butter.